Creatine-fatty acids

ABSTRACT

The present invention describes compounds produced from a creatine molecule and a fatty acid molecule. The compounds being in the form of creatine-fatty compounds bound by an amide linkage, or mixtures thereof produced by reacting creatine or derivatives thereof with an appropriate fatty acid in the presence of dichloromethane and a pyridine catalyst, previously reacted with a thionyl halide. The administration of such molecules provides supplemental creatine with enhanced bioavailability and the additional benefits conferred by the specific fatty acid.

RELATED APPLICATION

This application is a continuation of the applicant's co-pending U.S.application Ser. No. 11/676,630, filed Feb. 20, 2007 and claims benefitof priority thereto.

FIELD OF THE INVENTION

The present invention relates to structures and synthesis ofcreatine-fatty acid compounds bound via an amide linkage. Another aspectof the present invention relates to a compound comprising a creatinemolecule bound to a fatty acid, wherein the fatty acid is preferably asaturated fatty acid and bound to the creatine via an amide linkage.

BACKGROUND OF THE INVENTION

Creatine is a naturally occurring amino acid derived from the aminoacids glycine, arginine, and methionine. Although it is found in meatand fish, it is also synthesized by humans. Creatine is predominantlyused as a fuel source in muscle. About 65% of creatine is stored in themusculature of mammals as phosphocreatine (creatine bound to a phosphatemolecule).

Muscular contractions are fueled by the dephosphorylation of adenosinetriphosphate (ATP) to produce adenosine diphosphate (ADP). In theabsence of a mechanism to replenish ATP stores, the supply of ATP wouldbe totally consumed in 1-2 seconds. Phosphocreatine serves as a majorsource of phosphate from which ADP is regenerated to ATP. Within sixseconds following the commencement of exercise, muscular concentrationsof phosphocreatine drop by almost 50%. Creatine supplementation has beenshown to increase the concentration of creatine in the muscle (Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting andexercised muscle of normal subjects by creatine supplementation. ClinSci (Lond). 1992 September;83(3):367-74) and further, thesupplementation enables an increase in the resynthesis ofphosphocreatine (Greenhaff P L, Bodin K, Soderlund K, Hultman E. Effectof oral creatine supplementation on skeletal muscle phosphocreatineresynthesis. Am J Physiol. 1994 May;266(5 Pt 1):E725-30) leading to arapid replenishment of ATP within the first two minutes following thecommencement of exercise. Through this mechanism, creatine is able toimprove strength and reduce fatigue (Greenhaff P L, Casey A, Short A H,Harris R, Soderlund K, Hultman E. Influence of oral creatinesupplementation of muscle torque during repeated bouts of maximalvoluntary exercise in man. Clin Sci (Lond). 1993 May;84(5):565-71).

The beneficial effects of creatine supplementation with regard toskeletal muscle are apparently not restricted to the role of creatine inenergy metabolism. It has been shown that creatine supplementation incombination with strength training results in specific, measurablephysiological changes in skeletal muscle compared to strength trainingalone. For example, creatine supplementation amplifies the strengthtraining-induced increase of human skeletal satellite cells as well asthe number of myonuclei in human skeletal muscle fibres (Olsen S,Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen J L, Suetta C, Kjaer M.Creatine supplementation augments the increase in satellite cell andmyonuclei number in human skeletal muscle induced by strength training.J Physiol. 2006 Jun. 1;573(Pt 2):525-34). Satellite cells are the stemcells of adult muscle. They are normally maintained in a quiescent stateand become activated to fulfill roles of routine maintenance, repair andhypertrophy (Zammit P S, Partridge T A, Yablonka-Reuveni Z. The SkeletalMuscle Satellite Cell: The Stem Cell That Came In From the Cold. JHistochem Cytochem. 2006 Aug. 9). ‘True’ muscle hypertrophy can bedefined as “as an increase in fiber diameter without an apparentincrease in the number of muscle fibers, accompanied by enhanced proteinsynthesis and augmented contractile force” (Sartorelli V, Fulco M.Molecular and cellular determinants of skeletal muscle atrophy andhypertrophy. Sci STKE. 2004 Jul. 27;2004(244):re11). Postnatal musclegrowth involves both myofiber hypertrophy and increased numbers ofmyonuclei—the source of which are satellite cells (Olsen S, Aagaard P,Kadi F, Tufekovic G, Verney J, Olesen J L, Suetta C, Kjaer M. Creatinesupplementation augments the increase in satellite cell and myonucleinumber in human skeletal muscle induced by strength training. J Physiol.2006 Jun. 1;573(Pt 2):525-34).

Although creatine is used predominantly in muscle cells and most of thetotal creatine pool is found in muscle, creatine is actually synthesizedin the liver and pancreas. Thus, the musculature's creatineconcentration is maintained by the uptake of creatine from the bloodstream regardless of whether the source of creatine is endogenous, i.e.synthesized by the liver or pancreas, or dietary, i.e. natural foodsources or supplemental sources. The creatine content of an average 70kg male is approximately 120 g with about 2 g being excreted ascreatinine per day (Williams M H, Branch J D. Creatine supplementationand exercise performance: an update. J Am Coll Nutr. 1998June;17(3):216-34). A typical omnivorous diet supplies approximately 1 gof creatine daily, while diets higher in meat and fish will supply morecreatine. As a point of reference, a 500 g uncooked steak contains about2 g of creatine which equates to more than two 8 oz. steaks per day.Since most studies examining creatine supplementation employ dosagesranging from 2-20 g per day it is unrealistic to significantly increasemuscle creatine stores through merely food sources alone. Therefore,supplemental sources of creatine are an integral component ofincreasing, and subsequently maintaining supraphysiological, muscularcreatine levels.

Creatine supplementation, thus results in positive physiological effectson skeletal muscle, such as: performance improvements during briefhigh-intensity anaerobic exercise, increased strength and enhancedmuscle growth.

Creatine monohydrate is a commonly used supplement. Creatine monohydrateis soluble in water at a rate of 75 ml of water per gram of creatine.Ingestion of creatine monohydrate, therefore, requires large amounts ofwater to be co-ingested. Additionally, in aqueous solutions creatine isknown to convert to creatinine via an irreversible, pH-dependent,non-enzymatic reaction. Aqueous and alkaline solutions contain anequilibrium mixture of creatine and creatinine. In acidic solutions, onthe other hand, the formation of creatinine is complete. Creatinine isdevoid of the ergogenic beneficial effects of creatine. It is thereforedesirable to provide, for use in individuals, e.g. animals and humans,forms and derivatives of creatine with improved characteristics such asstability and solubility. Furthermore, it would be advantageous to do soin a manner that provides additional functionality as compared tocreatine monohydrate alone.

The manufacture of hydrosoluble creatine salts with various organicacids have been described. U.S. Pat. No. 5,886,040, incorporated hereinin its entirety by reference, purports to describe a creatine pyruvatesalt with enhanced palatability which is resistant to acid hydrolysis.

U.S. Pat. No. 5,973,199, purports to describe hydrosoluble organic saltsof creatine as single combination of one mole of creatine monohydratewith one mole of the following organic acids: citrate, malate, fumarateand tartarate individually. The resultant salts described therein areclaimed to be from 3 to 15 times more soluble, in aqueous solution, thancreatine itself.

U.S. Pat. No. 6,166,249, purports to describe a creatine pyruvic acidsalt that is highly stable and soluble. It is further purported that thepyruvate included in the salt may be useful to treat obesity, preventthe formation of free radicals and enhance long-term performance.

U.S. Pat. No. 6,211,407 purports to describe dicreatine and tricreatinecitrates and a method of making the same. These dicreatine andtricreatine salts are claimed to be stable in acidic solutions, thushampering the undesirable conversion of creatine to creatinine.

U.S. Pat. No. 6,838,562, purports to describe a process for thesynthesis of mono, di, or tricreatine orotic acid, thioorotic acid, anddihydroorotic acid salts which are claimed to have increased oralabsorption and bioavailability due to an inherent stability in aqueoussolution. It is further claimed that the heterocyclic acid portion ofthe salt acts synergistically with creatine.

U.S. Pat. No. 7,109,373, purports to describe creatine salts ofdicarboxylic acids with enhanced aqueous solubility.

The above disclosed patents recite creatine salts, methods of synthesisof the salts, and uses thereof. However, nothing in any of the disclosedpatents teaches, suggests or discloses a compound comprising a creatinemolecule bound to a fatty acid.

In addition to salts, creatine esters have also been described. U.S.Pat. No. 6,897,334 describes method for producing creatine esters withlower alcohols i.e. one to four carbon atoms, using acid catalysts. Itis stated that creatine esters are more soluble than creatine. It isfurther stated that the protection of the carboxylic acid moiety of thecreatine molecule by ester-formation stabilizes the compound bypreventing its conversion to creatinine. The creatine esters are said tobe converted into creatine by esterases i.e. enzymes that cleave esterbonds, found in a variety of cells and biological fluids.

Fatty acids are carboxylic acids, often containing a long, unbranchedchain of carbon atoms and are either saturated or unsaturated. Saturatedfatty acids do not contain double bonds or other functional groups, butcontain the maximum number of hydrogen atoms, with the exception of thecarboxylic acid group. In contrast, unsaturated fatty acids contain oneor more double bonds between adjacent carbon atoms, of the chains, incis or trans configuration.

The human body can produce all but two of the fatty acids it requires,thus, essential fatty acids are fatty acids that must be obtained fromfood sources due to an inability of the body to synthesize them, yet arerequired for normal biological function. The essential fatty acids beinglinoleic acid and a-linolenic acid.

Examples of saturated fatty acids include, but are not limited tomyristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearicor octadecanoic acid, arachidic or eicosanoic acid, behenic ordocosanoic acid, butyric or butanoic acid, caproic or hexanoic acid,caprylic or octanoic acid, capric or decanoic acid, and lauric ordodecanoic acid, wherein the aforementioned comprise from at least 4carbons to 22 carbons in the chain.

Examples of unsaturated fatty acids include, but are not limited tooleic acid, linoleic acid, linolenic acid, arachidonic acid, palmitoleicacid, eicosapentaenoic acid, docosahexaenoic acid and erucic acid,wherein the aforementioned comprise from at least 4 carbons to 22carbons in the chain.

Fatty acids are capable of undergoing chemical reactions common tocarboxylic acids. Of particular relevance to the present invention arethe formation of salts and the formation of esters. The majority of theabove referenced patents are creatine salts. These salts, esterificationvia carboxylate reactivity, may essentially be formed, as disclosed inU.S. Pat. No. 7,109,373, through a relatively simple reaction by mixinga molar excess of creatine or derivative thereof with an aqueousdicarboxylic acid and heating from room temperature to about 50° C.

Alternatively, a creatine-fatty acid may be synthesized through esterformation. The formation of creatine esters has been described (Dox A W,Yoder L. Esterification of Creatine. J. Biol. Chem. 1922, 67, 671-673).These are typically formed by reacting creatine with an alcohol in thepresence of an acid catalyst at temperatures from 35° C. to 50° C. asdisclosed in U.S. Pat. No. 6,897,334.

While the above referenced creatine compounds have attempted to addressissues such as stability and solubility in addition to, and in somecases, attempting to add increased functionality as compared to creatinealone, no description has yet been made of any creatine-fatty acidcompound, particularly a comprising a saturated fatty acid.

SUMMARY OF THE INVENTION

In the present invention, compounds are disclosed, where the compoundscomprise a molecule of creatine bound to a fatty acid, via an amidelinkage, and having a structure of Formula 1:

where:

R is an alkyl group, preferably saturated, and containing from about 3to a maximum of 21 carbons.

Another aspect of the invention comprises the use of a saturated fattyacid in the production of compounds disclosed herein.

A further aspect of the present invention comprises the use of anunsaturated fatty in the production of compounds disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, for the purposes of explanation, numerousspecific details are set forth in order to provide a thoroughunderstanding of the present invention. It will be apparent, however, toone skilled in the art that the present invention may be practicedwithout these specific details.

The present invention relates to routes of synthesis of creatine-fattyacid compounds bound via an amide linkage. In addition, specificbenefits are conferred by the particular fatty acid used to form thecompounds in addition to, and separate from, the creatine substituent.

As used herein, the term ‘fatty acid’ includes both saturated, i.e. analkane chain as known in the art, having no double bonds between carbonsof the chain and having the maximum number of hydrogen atoms, andunsaturated, i.e. an alkene or alkyne chain, having at least one doubleor alternatively triple bond between carbons of the chain, respectively,and further terminating the chain in a carboxylic acid as is commonlyknown in the art, wherein the hydrocarbon chain is not less then fourcarbon atoms. Furthermore, essential fatty acids are herein understoodto be included by the term ‘fatty acid’.

As used herein, “creatine” refers to the chemical N-methyl-N-guanylGlycine, (CAS Registry No. 57-00-1), also known as, (alpha-methylguanido) acetic acid, N-(aminoiminomethyl)-N-glycine,Methylglycocyamine, Methylguanidoacetic Acid, orN-Methyl-N-guanylglycine. Additionally, as used herein, “creatine” alsoincludes derivatives of creatine such as esters, and amides, and salts,as well as other derivatives, including derivatives havingpharmacoproperties upon metabolism to an active form.

According to the present invention, the compounds disclosed hereincomprise a creatine molecule bound to a fatty acid, wherein the fattyacid is preferably a saturated fatty acid. Furthermore, the creatine andfatty acid being bound by an amide linkage and having a structureaccording to Formula 1. The aforementioned compound being preparedaccording to the reaction as set forth for the purposes of thedescription in Scheme 1:

With reference to Scheme 1, in Step 1 an acyl halide (4) is produced viareaction of a fatty acid (2) with a thionyl halide (3).

In various embodiments of the present invention, the fatty acid of (2)is selected from the saturated fatty acid group comprising butyric orbutanoic acid, caproic or hexanoic acid, caprylic or octanoic acid,capric or decanoic acid, lauric or dodecanoic acid, myristic ortetradecanoic acid, palmitic or hexadecanoic acid, stearic oroctadecanoic acid, arachidic or eicosanoic acid, and behenic ordocosanoic acid.

In additional or alternative embodiments of the present invention, thefatty acid of (2) is selected from the unsaturated fatty acid groupcomprising oleic acid, linoleic acid, linolenic acid, arachidonic acid,palmitoleic acid, eicosapentaenoic acid, docosahexaenoic acid, anderucic acid.

Furthermore the thionyl halide of (3) is selected from the groupconsisting of fluorine, chlorine, bromine, and iodine, the preferredmethod using chlorine or bromine.

The above reaction proceeds under conditions of heat ranging betweenfrom about 35° C. to about 50° C. and stirring over a period from about0.5 hours to about 2 hours during which time the gases sulfur dioxideand acidic gas, wherein the acidic gas species is dependent on thespecies of thionyl halide employed, are evolved. Preferably, thereactions proceed at about 50° C. for about 1.25 hours.

Step 2 describes the addition of the prepared acyl halide (3) to asuspension of creatine (5) in dichloromethane (DCM), in the presence ofcatalytic pyridine (pyr), to form the desired creatine-fatty acid amide(1). The addition of the acyl halide takes place at temperatures betweenabout −15° C. and about 0° C. and with vigorous stirring. Followingcomplete addition of the acyl halide the reaction continues to stir andis allowed to warm to room temperature before the target amide compoundis isolated, the amide compound being a creatine fatty acid compound.

In various embodiments, according to aforementioned, using the saturatedfatty acids, the following compounds are produced:2-(3-butyryl-1-methylguanidino)acetic acid,2-(3-hexanoyl-1-methylguanidino)acetic acid,2-(1-methyl-3-octanoylguanidino)acetic acid,2-(3-decanoyl-1-methylguanidino)acetic acid,2-(3-dodecanoyl-1-methylguanidino)acetic acid,2-(1-methyl-3-tetradecanoguanidino)acetic acid,2-(1-methyl-3-palmitoylguanidino)acetic acid,2-(1-methyl-3-stearoylguanidino)acetic acid,2-(3-icosanoyl-1-methylguanidino)acetic acid, and2-(3-dodecanoyl-1-methylguanidino)acetic acid.

In additional embodiments, according to aforementioned, using theunsaturated fatty acids, the following compounds are produced:(Z)-2-(3-hexadec-9-enoyl-1-methylguanidino)acetic acid,(Z)-2-(1-methyl-3-oleoylguanidino)acetic acid,(Z)-2-(3-docos-13-enoyl-1-methylguanidino)acetic acid,2-(1-methyl-3-(9Z,12Z)-octadeca-9,12-dienoylguanidino)acetic acid,2-(1-methyl-3-(9Z,12Z,15Z)-octadeca-9,12,15-trienoylguanidino)aceticacid, 2-(1-methyl-3-(6Z,9Z,12Z)-octadeca-6,9,12-trienoylguanidino)aceticacid,2-(3-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoyl-1-methylguanidino)aceticacid,2-(3-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyl-1-methylguanidino)aceticacid,2-(3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyl-1-methylguanidino)aceticacid.

The following examples illustrate specific creatine-fatty acids androutes of synthesis thereof. One of skill in the art may envisionvarious other combinations within the scope of the present invention,considering examples with reference to the specification hereinprovided.

EXAMPLE 1

In a dry 2-necked, round bottomed flask, equipped with a magneticstirrer and fixed with a separatory funnel, containing 10.07 ml (130mmol) of thionyl bromide, and a water condenser, is placed 10.30 ml (65mmol) of octanoic acid. Addition of the thionyl bromide is completedwith heating to about 50° C. over the course of about 50 minutes. Whenaddition of the thionyl bromide is complete the mixture is heated andstirred for an additional hour. The water condenser is then replacedwith a distillation side arm condenser and the crude mixture isdistilled. The crude distillate in the receiving flask is thenfractionally distilled to obtain the acyl bromide, octanoyl bromide.This acyl bromide, 4.88 g (30 mmol), is put into a dry separatory funneland combined with 25 ml of dry dichloromethane for use in the next stepof the reaction.

In a dry 3-necked, round bottomed flask, equipped with a magneticstirrer, a thermometer, a nitrogen inlet tube and the dropping funnelcontaining the octanoyl bromide solution, 7.08 g (54 mmol) of creatineis suspended, with stirring, in 50 ml of dry dichloromethane. To thissuspension a catalytic amount (0.1 mmol) of pyridine is also added. Thesuspension is stirred in a dry ice and acetone bath to a temperature ofbetween to about −10° C. and 0° C. When the target temperature isreached the drop wise addition of octanoyl bromide is commenced.Addition of octanoyl bromide continues, with cooling and stirring, untilall of the octanoyl bromide is added, after which the reaction isallowed to warm to room temperature with constant stirring. The solutionis then filtered to remove any remaining creatine and the volatiledichloromethane and pyridine are removed under reduced pressure yielding2-(1-methyl-3-octanoylguanidino)acetic acid.

EXAMPLE 2

In a dry 2-necked, round bottomed flask, equipped with a magneticstirrer and fixed with a separatory funnel, containing 13.13 ml (180mmol) of thionyl chloride, and a water condenser, is placed 20.03 g (100mmol) of dodecanoic acid. Addition of the thionyl chloride is completedwith heating to about 45° C. over the course of about 30 minutes. Whenaddition of the thionyl chloride is complete the mixture is heated andstirred for an additional 45 minutes. The water condenser is thenreplaced with a distillation side arm condenser and the crude mixture isdistilled. The crude distillate in the receiving flask is thenfractionally distilled to obtain the acyl chloride, dodecanoyl chloride.This acyl chloride, 7.65 g (35 mmol), is put into a dry separatoryfunnel and combined with 50 ml of dry dichloromethane for use in thenext step of the reaction.

In a dry 3-necked, round bottomed flask, equipped with a magneticstirrer, a thermometer, a nitrogen inlet tube and the dropping funnelcontaining the dodecanoyl chloride solution, 7.34 g (56 mmol) ofcreatine is suspended, with stirring, in 50 ml of dry dichloromethane.To this suspension a catalytic amount (0.1 mmol) of pyridine is alsoadded. The suspension is stirred in a dry ice and acetone bath to atemperature of between about −15° C. and 0° C. When the targettemperature is reached the drop wise addition of dodecanoyl chloride iscommenced. Addition of dodecanoyl chloride continues, with cooling andstirring, until all of the dodecanoyl chloride is added, after which thereaction is allowed to warm to room temperature with constant stirring.The solution is then filtered to remove any remaining creatine, and thevolatile dichloromethane and pyridine are removed under reduced pressureyielding 2-(3-dodecanoyl-1-methylguanidino)acetic acid.

EXAMPLE 3

In a dry 2-necked, round bottomed flask, equipped with a magneticstirrer and fixed with a separatory funnel, containing 7.75 ml (100mmol) of thionyl bromide, and a water condenser, is placed 12.82 g (50mmol) of palmitic acid. Addition of the thionyl bromide is completedwith heating to about 50° C. over the course of about 50 minutes. Whenaddition of the thionyl bromide is complete the mixture is heated andstirred for an additional hour. The water condenser is then replacedwith a distillation side arm condenser and the crude mixture isdistilled. The crude distillate in the receiving flask is thenfractionally distilled to obtain the acyl bromide, palmitoyl bromide.This acyl bromide, 16.02 g (50 mmol), is put into a dry separatoryfunnel and combined with 75 ml of dry dichloromethane for use in thenext step of the reaction.

In a dry 3-necked, round bottomed flask, equipped with a magneticstirrer, a thermometer, a nitrogen inlet tube and the dropping funnelcontaining the palmitoyl bromide solution, 10.99 g (60 mmol) of creatineis suspended, with stirring, in 100 ml of dry dichloromethane. To thissuspension a catalytic amount (0.1 mmol) of pyridine is also added. Thesuspension is stirred in a dry ice and acetone bath to a temperature ofbetween to about −10° C. and 0° C. When the target temperature isreached the drop wise addition of palmitoyl bromide is commenced.Addition of palmitoyl bromide continues, with cooling and stirring,until all of the palmitoyl bromide is added, after which the reaction isallowed to warm to room temperature with constant stirring. The solutionis then filtered to remove any remaining creatine and the volatiledichloromethane and pyridine are removed under reduced pressure yielding2-(1-methyl-3-palmitoylguanidino)acetic acid.

EXAMPLE 4

In a dry 2-necked, round bottomed flask, equipped with a magneticstirrer and fixed with a separatory funnel, containing 7.88 ml (108mmol) of thionyl chloride, and a water condenser, is placed 20.44 g (60mmol) of docosanoic acid. Addition of the thionyl chloride is completedwith heating to about 45° C. over the course of about 30 minutes. Whenaddition of the thionyl chloride is complete the mixture is heated andstirred for an additional 70 minutes. The water condenser is thenreplaced with a distillation side arm condenser and the crude mixture isdistilled. The crude distillate in the receiving flask is thenfractionally distilled to obtain the acyl chloride, docosanoyl chloride.This acyl chloride, 21.60 g (60 mmol), is put into a dry separatoryfunnel and combined with 100 ml of dry dichloromethane for use in thenext step of the reaction.

In a dry 3-necked, round bottomed flask, equipped with a magneticstirrer, a thermometer, a nitrogen inlet tube and the dropping funnelcontaining the docosanoyl chloride solution, 12.59 g (96 mmol) ofcreatine is suspended, with stirring, in 100 ml of dry dichloromethane.To this suspension a catalytic amount (0.1 mmol) of pyridine is alsoadded. The suspension is stirred in a dry ice and acetone bath to atemperature of between about −15° C. and 0° C. When the targettemperature is reached the drop wise addition of docosanoyl chloride iscommenced. Addition of docosanoyl chloride continues, with cooling andstirring, until all of the docosanoyl chloride is added, after which thereaction is allowed to warm to room temperature with constant stirring.The solution is then filtered to remove any remaining creatine, and thevolatile dichloromethane and pyridine are removed under reduced pressureyielding 2-(3-dodecanoyl-1-methylguanidino)acetic acid.

EXAMPLE 5

In a dry 2-necked, round bottomed flask, equipped with a magneticstirrer and fixed with a separatory funnel, containing 13.15 ml (180mmol) of thionyl chloride, and a water condenser, is placed 28.45 ml(100 mmol) of palmitoleic acid. Addition of the thionyl chloride iscompleted with heating to about 40° C. over the course of about 30minutes. When addition of the thionyl chloride is complete the mixtureis heated and stirred for an additional 55 minutes. The water condenseris then replaced with a distillation side arm condenser and the crudemixture is distilled. The crude distillate in the receiving flask isthen fractionally distilled to obtain the acyl chloride,(Z)-hexadec-9-enoyl chloride. This acyl chloride, 10.95 g (40 mmol), isput into a dry separatory funnel and combined with 75 ml of drydichloromethane for use in the next step of the reaction.

In a dry 3-necked, round bottomed flask, equipped with a magneticstirrer, a thermometer, a nitrogen inlet tube and the dropping funnelcontaining the (Z)-hexadec-9-enoyl chloride solution, 8.39 g (64 mmol)of creatine is suspended, with stirring, in 75 ml of drydichloromethane. To this suspension a catalytic amount (0.1 mmol) ofpyridine is also added. The suspension is stirred in a dry ice andacetone bath to a temperature of between about −15° C. and 0° C. Whenthe target temperature is reached the drop wise addition of(Z)-hexadec-9-enoyl chloride is commenced. Addition of(Z)-hexadec-9-enoyl chloride continues, with cooling and stirring, untilall of the (Z)-hexadec-9-enoyl chloride is added, after which thereaction is allowed to warm to room temperature with constant stirring.The solution is then filtered to remove any remaining creatine, and thevolatile dichloromethane and pyridine are removed under reduced pressureyielding (Z)-2-(3-hexadec-9-enoyl-1-methylguanidino)acetic acid.

Thus while not wishing to be bound by theory, it is understood thatreacting a creatine or derivative thereof with a fatty acid orderivative thereof to form an amide can be used enhance thebioavailability of the creatine or derivative thereof by improvingstability of the creatine moiety in terms of resistance to hydrolysis inthe stomach and blood and by increasing solubility and absorption.Furthermore, it is understood that, dependent upon the specific fattyacid, for example, saturated fatty acids form straight chains allowingmammals to store chemical energy densely, or derivative thereof employedin the foregoing synthesis, additional fatty acid-specific benefits,separate from the creatine substituent, will be conferred.

Extensions and Alternatives

In the foregoing specification, the invention has been described with aspecific embodiment thereof; however, it will be evident that variousmodifications and changes may be made thereto without departing from thebroader spirit and scope of the invention.

1. A method for producing creatine fatty acids comprising at least thesteps of: mixing an excess of a thionyl halide with a fatty acid to forman acyl halide; said acyl halide then being added to a dichloromethanesuspension of creatine in the presence of a pyridine catalyst; andisolating the resulting creatine fatty acid.
 2. The method of claim 1wherein the halide of the thionyl halide is selected from the groupconsisting of fluorine, chlorine, bromine, and iodine.
 3. (canceled) 4.The method of claim 1 wherein the acyl halide is produced attemperatures from between about 35° C. to about 50° C.
 5. The method ofclaim 1 wherein the acyl halide and the suspension of creatine indichloromethane are reacted at temperatures from between about −15° C.to room temperature.
 6. The method of claim 1 wherein the creatine fattyacid is isolated by filtration followed by removal of thedichloromethane under reduced pressure.
 7. The method of claim 1 whereinthe creatine fatty acid has the general structure of:

wherein R is selected from the group consisting of alkanes and alkenes;said alkanes and alkenes having from 3 to 21 carbons.